USPTO Patents Application 09913752

Serial No. 09/913,752
Attorney Docket No. 104101.B700017

REMARKS

Applicants have cancelled claim 70 without prejudice.

Applicants have amended claims 80 and 82 to specify that the
hydroxypropyl methyl cellulose is a "low viscosity" hydroxypropyl methyl
cellulose. Support for this amendment is found e.g. on page 6, line 2 and the
examples.

Applicants have amended claim 80 to recite "...wherein the components
are combined to allow the glyceryl behenate and the hydroxypropyl
methylcellulose to form the matrix and the clarithromycin component is
dispersed within the matrix; ..." Support for this amendment is found, e.g., on
page 6, lines 12-13 "It has been found that by combining glyceryl behenate and
HPMC there was obtained an exceptionally effective matrix for sustaining and
controlling release of the active substance..."

Claims 70-72 and 76-84 stand rejected under 35 U.S.C. §112, first
paragraph for purportedly lacking written description. Applicants disagree and
in view of the following remarks and amendments to the claims request that the
Examiner reconsider and withdraw the rejection.

The Office states that the Applicants have support for 42.01% and 43.47%
clarithromycin but that the term "at least" and the term "about 42%" and "about
43%" are not supported by the specification. Although Applicants disagree,
Applicants have amended the claims by deleting "at least." As amended, the
claims comply with the written description requirement of §112, first paragraph.
While the specification may not recite explicitly "about 42%" or "about 43%" the
written description requirement does not require an explicit recitation of terms
recited in the claims. The essential goal of the description of the invention
requirement is to clearly convey the information that an applicant has invented
the subject matter which is claimed. There is no in haec verba requirement; the
newly added claim limitations must be supported in the specification but that

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support may be through express, imphcit, or inherent disclosure (see MPEP
§1302.01). Applicants have provided such support.

Applicants have disclosed that the daily dose of 500 mg clarithromycin has
to be imbedded in a relatively small matrix so that it is not hard to swallow
(Background of the Invention page 1, lines 15-16). Applicants have
demonstrated the production of tablets comprising 500mg clarithromycin; the
tablets comprise about 42% and about 43% clarithromycin, i.e. 42.01% for
example in Examples 2 and 3, and 43.47% in Examples 1, 4 and 5, respectively.
Presented with Applicants' teachings, a person of skill in the pharmaceutical art
would recognize that the inventor had possessions of pharmaceutical
preparations containing "about 42%" and "about 43%." An adequate written
description of the invention may be shown by any description of sufficient,
relevant, identifying characteristics so long as a person skilled in the art would
recognize that the inventor had possession of the claimed invention. See, e.g.,
Purdue Pharma L,P. v. Faulding Inc, 230 F.3d 1320, 1323, 56 USPQ2d 1481,
1483 (Fed. Cir. 2000) (the written description "inquiry is a factual one and must
be assessed on a case-by-case basis").

The foregoing demonstrates that Applicants have provided the necessary
showing to support adequate written description of the current claims and
request that the Examiner withdraw the rejection of the claims under 35 U.S.C.
§112, first paragraph

Claims 72, 76-78, and 80-83 stand rejected under 35 U.S.C. §103(a) for
purportedly being unpatentable over W095/22319 ("Briskin") in view of U.S.
Patent No. 5,811,120 ("Gibson") and for claim 82, METHOCEL and WO 98/42311
("Akiyama") are relied upon for evidence. Applicants disagree. The combination
of Briskin and Gibson, METHOCEL and Akiyama fail to teach or suggest the
claimed compositions.

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Applicants' claims recite a control release pharmaceutical formulation
comprising particular components, i.e., clarithromycin, glyceryl behenate and
low viscosity hydroxypropyl methyl cellulose (HPMC), in particular amounts,
which provide for a controlled release of clarithromycin over a 24 hour period.
The Office states that it would have been obvious to one of skill in the art at the
time the invention was made to combine the teachings of Briskin and Gibson and
utilize the instant hydrophilic binder (HPMC) (Office Action page 5, last
paragraph). The Office states that one would have been motivated to substitute
Briskin's hydrophilic binders (HPC and povidone), for HPMC with a reasonable
expectation of similar results because, the Office contends, Gibson teaches
HPMC, HPC and Povidone are conventional hydrophilic binders utilized in
pharmaceutical compositions (Office Action paragraph spanning pages 5-6).
However, even if one of skill in the pharmaceutical arts were to motivated to
substitute the "conventional binders" of Briskin's formula lb with HPMC then
the modified formula lb would comprise 36% HPMC, not 10.5% HPMC. At the
time of this invention those of skill in the art appreciated that Carbopol is also a
binder, see e.g., U.S. Patent No. 4,184,888, which states

"To further facilitate tableting, a conventional tableting
binder may optionally be employed .... Suitable binders
include, . . . hydroxypropylmethyl cellulose ... or a
carboxypolymethylene polymer (carbomer)."

Col. 3, lines 47 to 54.

Carbopol is a carbomer and thus a conventional binder and so Briskin
teaches a formulation comprising the "binder" in a total weight percent of 36.5%
(5.5% povidone, 5% HPC and 26% Carbopol), which is twice the maximum
amount of HPMC recited in Applicants' claims.

In addition, those of skill in the art appreciate that different binders have
different properties that confer different characteristics to pharmaceutical
formulations and without a description of the properties of the three different
binders in Briskin's formulation, Providone K90, a nondescript HPC and a

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nondescript Carbopol, one of skill in the art would not be motivated to simply
replace any of them with an HPMC with the expectation of similar effects.
Evidence that those of skill in the art do not consider all PVPs, HPCs and
HPMCs to be functionally equivalent, is found in U.S. Patent No. 5,126,145
("Evenstad"), which states "hydroxypropylmethylcelluloses vary in their
viscosity, methoxy content and hydroxypropoxyl content. Properties also vary."
(Col. 3, lines 5-7). Evidence that those of skill in the pharmaceutical arts do not
consider all HPCs and all HPMCs to be functionally equivalent is also found in
Akiyama who distinguishes "low-substituted HPC" from other HPCs and HPMCs
by describing it as "a material which swells a viscogenic agent" (see page 15,
lines 16-24) and then describing viscogenic agents to include Carbopol™, HPC
and HPMC. Evanstad also teaches the different functionality of high versus low
viscosity HPMC: high viscosity provides sustained release whereas a water-
soluble binder such a HPMC having binding properties has a much lower
viscosity; typically a viscosity of less than lOOcps such as Methocel E15. (Office
Action page 11, first paragraph). Thus, not all HPCs and HPMCs are
functionally equivalent. One of skill in the pharmaceutical arts could not
reasonably predict the effect that substituting an HPMC for one or more of
PVPK90, the uncharacterized HPC and the uncharacterized Carbopol would
have on the characteristics of Briskin's formula lb. Without any description of
the HPCs and the Carbopol's properties, one in the pharmaceutical could not
determine which other of a variety of compounds could be substituted for the
Briskin binders and still have similar characteristics to formula lb.

A factfinder should be aware, of course, of the distortion
caused by hindsight bias and must be cautious of arguments
reliant upon ex post reasoning. See Graham, 383 U, S., at 36
(warning against a "temptation to read into the prior art the
teachings of the invention in issue" and instructing courts to
"'guard against slipping into the use of hindsight"' (quoting
Monroe Auto Equipment Co, v, Heckethorn Mfg, & Supply
Co,, 332 F. 2d 406, 412 (CA6 1964))).

KSK V. Teleflex 550 U. S. (2007).

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While the Office has proposed that one of skill in the art would substitute
just two of the binders in Briskin's formulalb with a single HPMC to achieve an
HPMC amount of 10.5%, such a substitution, considered within the context of
the knowledge available to those of skill in the art at the time of the invention,
would only be made in hindsight in light of Applicants' disclosure.

Thus, in view of the knowledge available to those of skill in the art at the
time of this invention, Briskin in combination with Gibson fails to provide the
necessary guidance and motivation for one of skill in the art to replace only two
of Briskin's three "conventional binders" with any HPMC with the expectation of
obtaining similar properties; and even if one were to replace Briskin's three
"conventional binders" with an HPMC, even a low viscosity HPMC, the amount
of HPMC would be twice the maximum amount recited in Applicants' claims.
Thus Briskin in combination with Gibson considered within the state of the art,
does not teach or suggest Applicants' invention.

Regarding claim 82, even if the formation of a viscous layer is a natural
property of HPMC, the combination of Briskin and Gibson does not teach or
suggest a formulation comprising a low viscosity HPMC and as such Briskin and
Gibson also fail to teach or suggest claim 82.

In view of the foregoing remarks, Applicants request that the Examiner
reconsider and withdraw the rejection of Claims 72, 76-78, 80-83 under 35 U.S.C.
§ 103(a) for purportedly being unpatentable over Briskin in view of Gibson.

Claims 70-71 stand rejected under 35 U.S.C. § 103(a) for purportedly being
unpatentable over Briskin in view of Gibson as evidenced by METHOCEL™ and
Akiyama for claim 82 and further in view of US Patent No. 5,126,145
("Evenstad"). Applicants respectfully disagree.

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The Office concludes that it would have been obvious to one of ordinary
skill in the art at the time the invention was made to combine the teachings of
Briskin, Gibson and Evenstad and specifically utilize a low viscosity HPMC and
that "a skilled artisan would have been motivated to use a low viscosity HPMC
with a reasonable expectation of similar results since both Briskin and Gibson
teach the use of the cellulose derivative for its binding property and Evenstad
teaches the low viscosity cellulose derivative provide this function" (Office Action
page 11). As discussed above, Evenstad and Akiyama demonstrate that all
HPCs and HPMCs are not functionally equivalent and thus without a
description of the HPCs and Carbopols in Briskin's formula lb, the skilled
artisan would not simply replace one or more of Briskin's "binders" with just
another "binder" and expect to obtain similar results. And even if one of skill in
the arts substituted the PVP, HPC and Carbopol with HPMC, such a
substitution would not produce Applicants' claimed control-release formulations
because the amount of HPMC needed for such a substitution, 36.5%, would be
more than twice the maximum amount recited in Applicants' claims.

Furthermore, Evanstad is directed to improved controlled release
formulations and Evenstad's solution for making the controlled release
formulation is to use a high viscosity HPMC to achieve controlled or sustained
release. Thus, Evenstad teaches away from using a low viscosity HPMC to
produce a controlled release formulation, as required in Applicants' claims.

. "When the prior art teaches away from combining certain
known elements, discovery of a successful means of
combining them is more likely non-obvious . . . ."

KSR Int'l Co, V Teleflex Inc,
550 U.S. _ (2007).

The foregoing demonstrates that considered within the context of the state
of the art at the time of filing, the combination of Briskin, Gibson, and Evenstad
fails to teach or suggest the invention as claimed. Applicants request that the
Examiner reconsider and withdraw the rejection of claims under 35 U.S.C. §103

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over Briskin in view of Gibson as evidenced by METHOCELtm and WO 98/42311
for claim 82 and further in view of US Patent No. 5,126,145 (Evenstad).

Claim 79 stands rejected under 35 U.S.C. § 103(a) for purportedly being
unpatentable over Briskin in view of Gibson as evidenced by METHOCEL™ and
Akiyama for claim 82 further in view of US patent No. 5,656,295 ("Khan").
Applicants disagree.

The failure of Briskin, Gibson, METHOCEL™ and Akiyama to teach or
suggest the claimed formulations have been discussed above. The deficiencies of
these references are not compensated for by Khan. Khan simply teaches a
delivery system coated with a coating layer. Khan fails to teach or suggest the
particular formulation recited in Applicants' claim and without such a teaching
or suggestion, its simple generic teaching that one may coat a delivery system
combined with the disclosures of Briskin and Gibson, fails to render the claimed
formulations obvious.

In view of the forgoing remarks. Applicants request that the Examiner
reconsider and withdraw the rejection of claim 79 under 35 U.S.C. § 103(a) in
view of Briskin, Gibson, and Khan.

Claims 70-72, 76-84 stand rejected under 35 U.S.C. §103(a) for
purportedly being unpatentatble over Akiyama in view of WO 98/14176
("Farah"), US equivalent Patent No. 6,194,005. Applicants respectfully disagree.

Applicants claim a controlled-release formulation comprising glyceryl
behenate, low viscosity hydroxypropyl methyl cellulose and clarithromycin in
particular amounts, i.e., 10-36%, 13-18% and about 42% or about 43%
respectively. In contrast, Akiyama teaches broad genera of compounds and of
weight percentages including, e.g.:

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a swelling material that swells a viscogenic agent or
accelerates the swell of a viscogenic agent caused by water
(page 15, lines 16-19), in an amount of about 0.5 to 50 weight
% (page 15, line 25-27)

any type of viscogenic agent (page 17, lines 11-15), preferably
having a viscosity of 3 to 50,000cps (page 17, lines 20-22), in
amounts of about 0.005 to about 99% (page 19, lines 5-7),

a polyglycerol fatty acid ester in an amount of 5-98% (page
12, lines 1-2),

a antimicrobial substance in an amount of 0.0005-95% (page
26, lines 13-15),

an optional coating material, and
surfactants.
The Office states

"Akiyama does not specify the glycerol fatty acid ester.
Farah teaches a method for preparing a pharmaceutical
composition with modified release of the active principle,
comprising a matrix as lipid matrix agent, of an ester of
behenic acid or alcohol. ...The lipid is used in an amount of 1-
15% ...glycerol behenate is the preferred lipid for the matrix"

(Office Action paragraph spanning
pages 14-15)

and concludes that it would have been obvious to one of skill in the art at the
time the invention was made to combine the teachings of Akiyama and Farah
and utilize glyceryl behenate in Akiyama's composition. Yet Akiyama
acknowledges that the selection of polyglycerol fatty acid ester is dependent on
many factors, including the identity of the active compound and viscogenic agent:

"the proper polyglycerol fatty acid ester can be selected with
reference to the particular active ingredient (e.g., anti-HP
agent, etc.), viscogenic agent, swelling material (e.g., curdlan,
and/or low -substituted hydroxypropylcellulose, etc.), the
particular combination thereof, and the objective form of the
composition" (sentence spanning page 10-11).

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Farah does not prepare any formulations with clarithromycin. Farah also
demonstrates that their preparation method and the composition of the
formulation could enhance or inhibit the release of active agent. Farah does not
present any analysis of glyceryl behenate with clarithromycin. Therefore one of
skill in the art based on Farah would have no reasonable expectation regarding
how this active agent would interact with glyceral behenate.

Furthermore, Applicants' claims require a low viscosity HPMC at 13-18
weight percent. Akiyama's teaching that the viscogenic agent "may be selected
from any agent that is capable of swelling in water." does not provide any sort of
guidance as to the type of agent one should use. Akiyama's more specific
teaching that "a suitable synthetic polymer has a viscosity 3-50,000cps and a
basic or acidic polymer has a viscosity of about 100 to about 50,000cps" (see page
17, lines 20-22 and lines 24-28) is also insufficient to guide one of skill in the
pharmaceutical arts to the claimed controlled release formulation comprising the
particular amounts of low-viscosity HPMC, glyceral behenate and clarithromycin
as recited in Applicants' claims. The Office previously cited Evenstad for
teaching the high viscosity HPMCs are useful for sustaining action. Thus one
having the knowledge available in the pharmaceutical arts would not be
motivated to use a low viscosity rather than a high viscosity HPMC for the
formulations in view of Akiyama's general disclosure. Given the broad scope of
Akiyama's recited genera, even if the polyglycerol fatty acid is substituted by a
glyceral behenate, combining Akiyama's genera would present countless
formulation permutations and one of skill in the art could not reasonably predict
which would be a suitable controlled release formulation for clarithromycin. As
such Akiyama combined with Farah does not teach or suggest Applicants'
particularly claimed control-release formulation.

In view of the forgoing remarks and amendments to the claims. Applicants
request that the Office reconsider and withdraw the rejection of the claims under
35 U.S.C. §103 over Akiyama in view of Farah.

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If there are any questions regarding this amendment or the apphcation in
general, a telephone call to the undersigned would be appreciated since this
should expedite the prosecution of the application for all concerned.

If necessary to effect a timely response, this paper should be considered as
a petition for an Extension of Time sufficient to effect a timely response, and

please charge any deficiency in fees or credit any overpayments to Deposit
Account No. 05-1323 (Docket #104101.B700017).

CROWELL & MORING LLP
Intellectual Property Group
P.O. Box 14300
Washington, DC 20044-4300
Telephone No.: (202) 624-2500
Facsimile No.: (202) 628-8844
MAS/mas

Respectfully submitted.

December 1, 2008

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